Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.
Phase I biodistribution and pharmacokinetic study of Lewis Y-targeting immunoconjugate CMD-193 in patients with advanced epithelial cancers.
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DOI：
10.1158/1078-0432.ccr-09-0536
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发表时间：
2009-11-01
期刊：
影响因子：
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通讯作者：
Scott AM
中科院分区：
文献类型：
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作者：
Herbertson RA;Tebbutt NC;Lee FT;MacFarlane DJ;Chappell B;Micallef N;Lee ST;Saunder T;Hopkins W;Smyth FE;Wyld DK;Bellen J;Sonnichsen DS;Brechbiel MW;Murone C;Scott AM
该I期研究探索了免疫缀合物CMD-193 [与加利车霉素缀合的人源化抗路易斯Y（Ley）抗体]在表达Ley抗原的晚期癌症患者中的生物分布和药代动力学。主要目的是确定CMD-193的生物分布和药代动力学。次要目的包括缓解率和肿瘤代谢的变化。患有进行性、可测量和Ley阳性恶性肿瘤的患者有资格入组1.0和2.6 mg/m2两个剂量队列之一。第一个循环用111 In示踪，用于使用γ照相机成像的生物分布评估。随后的周期每3周给药一次，最多6个周期，取决于毒性和反应。药代动力学分析基于放射性测定和ELISA。9例患者入组研究。生物分布图像显示初始血池活性，随后在第2天显著增加肝脏摄取，并且所有患者的血液清除速度都很快。所有患者的肿瘤均呈低摄取。111 In-CMD-193的总体T½β为102.88 ± 35.67小时，两个剂量水平之间无统计学显著差异。1例患者在4个周期后的18F-氟脱氧葡萄糖-正电子发射断层扫描（18F-FDG PET）中出现部分代谢反应，但未观察到放射学反应。骨髓抑制和对肝功能的影响是最显著的不良反应。与亲本抗体hu 3S 193的先前研究相比，CMD-193显示快速血液清除和增加的肝摄取。这些结果强调了生物分布和药效学评估在新生物制剂早期研究中的重要性，以帮助临床开发。(Clin Cancer Res 2009;15（21）：6709-15）。
This phase I study explored the biodistribution and pharmacokinetics of the immunoconjugate CMD-193 [a humanized anti–Lewis Y (Ley) antibody conjugated with calicheamicin in patients with advanced cancers expressing the Ley antigen. The primary objectives were to determine biodistribution and pharmacokinetics of CMD-193. Secondary objectives included response rates and change in tumor metabolism. Patients with progressive, measurable, and Ley positive malignancies were eligible for enrollment in one of two dose cohorts, 1.0 and 2.6 mg/m2. The first cycle was trace labeled with 111In for biodistribution assessment using γ camera imaging. Subsequent cycles were administered every 3 weeks up to a maximum of six cycles, depending on toxicity and response. Pharmacokinetic analysis was based on radioassay and ELISA. Nine patients were enrolled in the study. Biodistribution images showed initial blood pool activity, followed by markedly increased hepatic uptake by day 2, and fast blood clearance in all patients. There was low uptake in tumor in all patients. The overall T½β of 111In-CMD-193 was 102.88 ± 35.67 hours, with no statistically significant difference between the two dose levels. One patient had a partial metabolic response on 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG PET) after four cycles, but no radiological responses were observed. Myelosuppression and effects on liver function were the most significant adverse effects. CMD-193 shows rapid blood clearance and increased hepatic uptake compared with prior studies of the parental antibody hu3S193. These results highlight the importance of biodistribution and pharmacodynamic assessment in early phase studies of new biologics to assist in clinical development. (Clin Cancer Res 2009;15(21):6709–15).